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Metabolic and Transcriptional Profiling of a Lethal Tumor Micro‐Environment
Author(s) -
Lisanti Michael P.,
Sotgia Federica
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.225.1
Subject(s) - mitophagy , autophagy , oxidative stress , breast cancer , cancer research , stromal cell , downregulation and upregulation , biology , medicine , cancer , endocrinology , apoptosis , gene , biochemistry
Loss of stromal Cav‐1 in the fibroblast compartment is associated with early tumor recurrence, and lymph‐node metastasis, resulting in poor clinical outcome in breast cancer patients. Here, we have used Cav‐1 (−/−) mice as a pre‐clinical model for this “lethal tumor micro‐environment.” Metabolic profiling of Cav‐1 (−/−) mammary fat pads revealed the upregulation of nearly 100 metabolites, indicative of a major catabolic phenotype. Our results are consistent with induction of oxidative stress, mitochondrial dysfunction, and autophagy/mitophagy. The two most prominent metabolites that emerged from this analysis were ADMA (asymmetric dimethyl arginine) and BHB (beta‐hydroxybutyrate), which are markers of oxidative stress and mitochondrial dysfunction. Transcriptional profiling of Cav‐1 (−/−) stromal cells and human tumor stroma from breast cancer patients directly supported an association with oxidative stress, mitochondrial dysfunction, and autophagy/mitophagy, as well as ADMA and ketone production. MircoRNA profiling of Cav‐1 (−/−) stromal cells revealed the upregulation of two key cancer‐related miR's, miR‐31 and miR‐34c. Consistent with our metabolic findings, these miR's are associated with oxidative stress and hypoxia. Thus, we have identified candidate biomarkers that could be used to identify high‐risk cancer patients.